Post-natal nutrition, intestinal dysbiosis and pulmonary hypertension in premature infants: the role of the developing gut-lung axis

早产儿的产后营养、肠道菌群失调和肺动脉高压：肠肺轴发育的作用

• 批准号: 9762153
• 负责人: Mark Alan Underwood
• 金额: $ 19.63万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-10 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762153
• 关键词: Address; Adult; Animal Model; Animals; Antibodies; Attenuated; Birth; Blood Vessels; Bronchopulmonary Dysplasia; Caring; Cell Wall; Cerebral Palsy; Chronic lung disease; Clinical; Cognitive; Complication; Coronary Arteriosclerosis; Data; Development; Dietary Intervention; Disease; Drops; Energy Intake; Engineered Probiotics; Enterobacteriaceae; Exposure to; Fatty Acids; Fetal Growth Retardation; Future; Gases; Gastrointestinal tract structure; Growth; Growth Factor; Heart; Hospitalization; Hyperoxia; Hypertension; Infant; Intervention; Intestines; Life; Link; Lipopolysaccharides; Lipoproteins; Lung; Lung diseases; Metabolic syndrome; Microbe; Milk; Modeling; Molecular; Morbidity - disease rate; Mothers; Necrotizing Enterocolitis; Neonatal; Neonatal Intensive Care Units; Nutrient; Obesity; Oligosaccharides; Organism; Pathway interactions; Patients; Pattern; Phenotype; Physiologic Thermoregulation; Placenta; Premature Birth; Premature Infant; Prevention; Probiotics; Process; Pulmonary Hypertension; Rattus; Reporting; Retinopathy of Prematurity; Risk; Rodent Model; Role; Sepsis; Severities; Side; Small Intestines; TLR4 gene; Testing; Translations; Weight; attenuation; base; dysbiosis; experimental study; gut microbiota; gut-lung axis; hypercholesterolemia; improved outcome; in utero; innovation; novel; nutrition; osteopontin; pathogen; postnatal; premature; prevent; pup

Post-natal nutrition, intestinal dysbiosis and pulmonary hypertension in premature infants: the role of the developing gut-lung axis Abstract Poor growth in the first weeks and months of life is very common in very premature infants with up to 80% of extremely premature infants dropping below the 10th percentile for weight during hospitalization in the Neonatal Intensive Care Unit, a complication referred to as post-natal growth restriction (PNGR). As emphasis has shifted in the last decades from survival to improving outcomes, it has become clear that PNGR is associated with increased risk of much of the morbidity associated with prematurity including pulmonary hypertension (PH), neurodevelopmental delays, necrotizing enterocolitis, sepsis, retinopathy of prematurity, and chronic lung disease (also known as bronchopulmonary dysplasia). Furthermore PNGR in premature infants is also associated with many adult diseases that have been demonstrated to result from fetal growth restriction in term infants including metabolic syndrome, obesity, and hypertension. Simply maximizing caloric intake in the first weeks of life has been somewhat helpful, however PNGR remains very common due to the incredible challenges associated with immaturity of the gastrointestinal tract. We propose novel studies in an animal model of PNGR to discover the mechanisms by which PNGR triggers PH (the most compelling clinical example of alteration of the developing gut-lung axis). We utilize a rat model of PNGR based upon manipulation of the number of pups cared for by a single dam. The PH phenotype associated with PNGR is worsened by exposure to hyperoxia mimicking a common clinical situation (the extremely premature infant with severe lung disease and poor growth). We present preliminary data supporting two groundbreaking observations: first, that PNGR is associated with intestinal dysbiosis and that administration of probiotic microbes prevents PNGR-associated PH and second, that enhanced nutrition is protective against the damaging effect of hyperoxia. In aim 1 we propose experiments to define the developmental window in which probiotics or enhanced nutrition prevent PH. In aim 2 we propose to determine whether the TLR4/MyD88/NFκB pathway is essential in this model. Our novel observation that Enterobacteriaceae are significantly increased in the small intestine with PNGR suggests the potential role of TLR4 in the developing gut-lung axis as the cell wall of these Gram negative organisms contains abundant lipo-polysaccharide (one of the key pathogen associated molecular patterns recognized by TLR4). A mechanistic understanding of these processes is essential to prevention of both infant and adult complications of PNGR.

早产儿出生后营养、肠道生态失调和肺动脉高压的作用 发育中的肠肺轴 摘要 在生命的头几周和几个月内发育不良在极早产儿中非常普遍，高达80%的 新生儿住院期间体重降至10%以下的极早产儿 重症监护病房，一种称为产后生长受限(PNGR)的并发症。正如强调的那样 在过去的几十年里，PNGR从生存转向改善预后，这一点已经变得明显 与早产相关的大部分发病率的风险增加，包括肺动脉高压 (PH值)、神经发育迟缓、坏死性小肠结肠炎、败血症、早产儿视网膜病变和慢性肺 疾病(也称为支气管肺发育不良)。此外，早产儿的PNGR也 与许多成人疾病有关，这些疾病已被证明是由足月胎儿生长受限引起的 婴儿包括代谢综合征、肥胖和高血压。只需在第一时间最大限度地增加卡路里摄入量 几周的生活有一定的帮助，但PNGR仍然非常常见，因为令人难以置信的 与胃肠道不成熟相关的挑战。我们建议在动物身上进行新的研究 PNGR模型，以发现PNGR触发PH的机制(最引人注目的临床 发育中的肠肺轴改变的例子)。我们利用PNGR的大鼠模型，基于 操纵一座水坝照顾的幼崽数量。与PNGR相关的PH表型为 由于暴露在高氧环境中而恶化，类似于一种常见的临床情况(极早产儿 严重的肺部疾病和生长不良)。我们提供的初步数据支持两个开创性的 观察：首先，PNGR与肠道菌群失调和益生菌的使用有关 微生物可以预防PNGR相关的PH，第二，加强营养可以保护 高氧的损害作用。在目标1中，我们提出了定义发育窗口的实验，在该窗口中 益生菌或强化营养可以预防PH。在目标2中，我们建议确定 TLR4/MYD88/NFκB通路在该模型中起重要作用。我们的新观察表明，肠杆菌科是 PNGR患者小肠组织中TLR4的表达显著增加，提示TLR4在发育过程中可能起重要作用。 肠肺轴作为革兰氏阴性菌的细胞壁，含有丰富的脂多糖(其中一种 TLR4识别的关键病原体相关分子模式)。对这些的机械性理解 手术过程对预防婴幼儿和成人PNGR并发症至关重要。